Low glucose-enhanced TRAIL cytotoxicity is mediated through the ceramide-Akt-FLIP pathway
| Autor: | Yong J. Lee, Seon Young Nam, Andrew A. Amoscato |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Male
Cancer Research medicine.medical_specialty Programmed cell death Ceramide Spectrometry Mass Electrospray Ionization Cell Survival CASP8 and FADD-Like Apoptosis Regulating Protein Apoptosis Biology Adenocarcinoma Protein Serine-Threonine Kinases Ceramides Receptors Tumor Necrosis Factor Dephosphorylation TNF-Related Apoptosis-Inducing Ligand chemistry.chemical_compound Internal medicine Proto-Oncogene Proteins Genetics medicine Tumor Cells Cultured Humans Cytotoxicity Molecular Biology Protein kinase B Tumor microenvironment Membrane Glycoproteins Tumor Necrosis Factor-alpha Intracellular Signaling Peptides and Proteins Prostatic Neoplasms Enzyme Activation Receptors TNF-Related Apoptosis-Inducing Ligand Endocrinology Glucose chemistry Flip Caspases Cancer research Poly(ADP-ribose) Polymerases Apoptosis Regulatory Proteins Carrier Proteins Proto-Oncogene Proteins c-akt |
| Zdroj: | Oncogene. 21(3) |
| ISSN: | 0950-9232 |
| Popis: | To examine whether the tumor microenvironment alters cytokine-induced cytotoxicity, human prostate adenocarcinoma DU-145 cells were exposed to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and/or glucose deprivation, a common characteristic of the tumor microenvironment. TRAIL alone reduced cell survival in a dose-dependent manner. Glucose deprivation alone induced no cytotoxicity within 4 h. However, the combination of TRAIL (50 ng/ml) and glucose deprivation for 4 h increased cell death and PARP cleavage by promoting activation of caspase-8 and caspase-3, relative to that of TRAIL alone. Similar results were observed in human colorectal carcinoma CX-1 cells. Data from immunoblotting analysis reveal that glucose deprivation-enhanced TRAIL cytotoxicity is inversely related to the intracellular level of FLICE inhibitory protein (FLIP) but not that of death receptor 5 (DR5). Results from mass spectrometry show that glucose deprivation elevates ceramide. The elevation of ceramide may cause dephosphorylation of Akt and maintain dephosphorylation of Akt in the presence of TRAIL and then subsequently down-regulate the expression of FLIP. Taken together, the present studies suggest that glucose deprivation enhances TRAIL-induced cytotoxicity through the ceramide-Akt-FLIP pathway. |
| Databáze: | OpenAIRE |
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